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    Clinical Trial Results:
    A Phase 1, Single Dose, 4-Period Crossover Study to Assess the Bioavailability of an Mirabegron Oral Suspension Relative to the Mirabegron Prolonged Release Tablet and to Assess the Effect of Food on the Pharmacokinetics of Mirabegron Oral Suspension in Healthy Young Male and Female Subjects

    Summary
    EudraCT number
    		 2014-001446-24
    Trial protocol
    		 DE  
    Global end of trial date
    21 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2016
    First version publication date
    18 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    178-CL-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe BV
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333 BE
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000597-PIP03-15 EMEA-000597-PIP02-10
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the bioavailability of 50 mg mirabegron oral suspension relative to that of the 50 mg mirabegron modified release tablet when dosed under fasted conditions.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Healthy male and female participants were enrolled at one site in Germany and were resident for a period of 5 days in each of 4 treatment periods. On day -1 of each treatment period, the subjects were admitted to the clinical unit and discharged on day 4. Ambulant visits occurred on days 5, 6, 7, 9 and 11.

    Pre-assignment
    Screening details
    		 Participants who fulfilled all eligibility criteria were randomized to 1 of 4 treatment sequences (in first treatment period only) following the William's design in this 4-period crossover study. There was a washout period of at least 14 days between treatment periods.

    Period 1
    Period 1 title
    Overall Study (Periods 1-4) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This is an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Sequence 1: ACBD
    Arm description
    		 Participants who received a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 1, a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 2, a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 3 and a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mirabegron 50 mg oral suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg oral suspension on day 1 in one of 4 treatment periods, depending on their treatment sequence. Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL and given to participants. Doses were administered under fasted conditions (overnight fast of at least 10 hours prior to dosing and 4 hours after dosing).

    Investigational medicinal product name
    Mirabegron 50 mg modified release tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg modified release tablet orally on day 1 in one of 4 treatment periods, depending on their treatment sequence. Doses were administered under fasted conditions (overnight fast of at least 10 hours prior to dosing and 4 hours after dosing).

    Investigational medicinal product name
    Mirabegron 50 mg oral suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg oral suspension on day 1 in one of 4 treatment periods, depending on their treatment sequence. Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL and given to participants. Doses were administered with food (dosing done 30 minutes after completion of the light breakfast and a light lunch 2 hours after).

    Investigational medicinal product name
    Mirabegron 50 mg modified release tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg modified release tablet orally on day 1 in one of 4 treatment periods, depending on their treatment sequence. Doses were administered with food (dosing was done 30 minutes after completion of the light breakfast and a light lunch 2 hours after).

    Arm title
    		 Treatment Sequence 2: BADC
    Arm description
    		 Participants who received a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 1, a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 2, a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 3 and a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mirabegron 50 mg oral suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg oral suspension on day 1 in one of 4 treatment periods, depending on their treatment sequence. Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL and given to participants. Doses were administered under fasted conditions (overnight fast of at least 10 hours prior to dosing and 4 hours after dosing).

    Investigational medicinal product name
    Mirabegron 50 mg modified release tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg modified release tablet orally on day 1 in one of 4 treatment periods, depending on their treatment sequence. Doses were administered under fasted conditions (overnight fast of at least 10 hours prior to dosing and 4 hours after dosing).

    Investigational medicinal product name
    Mirabegron 50 mg oral suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg oral suspension on day 1 in one of 4 treatment periods, depending on their treatment sequence. Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL and given to participants. Doses were administered with food (dosing done 30 minutes after completion of the light breakfast and a light lunch 2 hours after).

    Investigational medicinal product name
    Mirabegron 50 mg modified release tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg modified release tablet orally on day 1 in one of 4 treatment periods, depending on their treatment sequence. Doses were administered with food (dosing was done 30 minutes after completion of the light breakfast and a light lunch 2 hours after).

    Arm title
    		 Treatment Sequence 3: CDAB
    Arm description
    		 Participants who received a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 1, a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 2, a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 3 and a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mirabegron 50 mg oral suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg oral suspension on day 1 in one of 4 treatment periods, depending on their treatment sequence. Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL and given to participants. Doses were administered under fasted conditions (overnight fast of at least 10 hours prior to dosing and 4 hours after dosing).

    Investigational medicinal product name
    Mirabegron 50 mg modified release tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg modified release tablet orally on day 1 in one of 4 treatment periods, depending on their treatment sequence. Doses were administered under fasted conditions (overnight fast of at least 10 hours prior to dosing and 4 hours after dosing).

    Investigational medicinal product name
    Mirabegron 50 mg oral suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg oral suspension on day 1 in one of 4 treatment periods, depending on their treatment sequence. Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL and given to participants. Doses were administered with food (dosing done 30 minutes after completion of the light breakfast and a light lunch 2 hours after).

    Investigational medicinal product name
    Mirabegron 50 mg modified release tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg modified release tablet orally on day 1 in one of 4 treatment periods, depending on their treatment sequence. Doses were administered with food (dosing was done 30 minutes after completion of the light breakfast and a light lunch 2 hours after).

    Arm title
    		 Treatment Sequence 4: DBCA
    Arm description
    		 Participants who received a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 1, a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 2, a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 3 and a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mirabegron 50 mg oral suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg oral suspension on day 1 in one of 4 treatment periods, depending on their treatment sequence. Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL and given to participants. Doses were administered under fasted conditions (overnight fast of at least 10 hours prior to dosing and 4 hours after dosing).

    Investigational medicinal product name
    Mirabegron 50 mg modified release tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg modified release tablet orally on day 1 in one of 4 treatment periods, depending on their treatment sequence. Doses were administered under fasted conditions (overnight fast of at least 10 hours prior to dosing and 4 hours after dosing).

    Investigational medicinal product name
    Mirabegron 50 mg oral suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg oral suspension on day 1 in one of 4 treatment periods, depending on their treatment sequence. Mirabegron was provided as granules and reconstituted with vehicle in bottle and was prepared into a modified release oral suspension 2 mg/mL and given to participants. Doses were administered with food (dosing done 30 minutes after completion of the light breakfast and a light lunch 2 hours after).

    Investigational medicinal product name
    Mirabegron 50 mg modified release tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq®, Betmiga™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single dose of mirabegron 50 mg modified release tablet orally on day 1 in one of 4 treatment periods, depending on their treatment sequence. Doses were administered with food (dosing was done 30 minutes after completion of the light breakfast and a light lunch 2 hours after).

    Number of subjects in period 1
    		Treatment Sequence 1: ACBD Treatment Sequence 2: BADC Treatment Sequence 3: CDAB Treatment Sequence 4: DBCA
    Started
    7
    6
    6
    6
    Completed Treatment Period 1
    6
    6
    6
    6
    Completed Treatment Period 2
    6
    6
    6
    6
    Completed Treatment Period 3
    6
    5
    6
    6
    Completed Treatment Period 4
    6
    5
    5
    6
    Completed
    6
    5
    5
    6
    Not completed
    1
    1
    1
    0
         Consent withdrawn by subject
    -
    1
    -
    -
         Protocol violation
    1
    -
    -
    -
         Adverse event
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Sequence 1: ACBD
    Reporting group description
    		 Participants who received a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 1, a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 2, a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 3 and a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 4.

    Reporting group title
    Treatment Sequence 2: BADC
    Reporting group description
    		 Participants who received a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 1, a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 2, a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 3 and a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 4.

    Reporting group title
    Treatment Sequence 3: CDAB
    Reporting group description
    		 Participants who received a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 1, a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 2, a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 3 and a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 4.

    Reporting group title
    Treatment Sequence 4: DBCA
    Reporting group description
    		 Participants who received a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 1, a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 2, a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 3 and a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 4.

    Reporting group values
    		 Treatment Sequence 1: ACBD Treatment Sequence 2: BADC Treatment Sequence 3: CDAB Treatment Sequence 4: DBCA Total
    Number of subjects
    		 7 6 6 6
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 22.9 ( 1.3 ) 22.2 ( 1.6 ) 21.7 ( 3 ) 22.5 ( 2.2 ) -
    Gender categorical
    Units:
        Male
    		 3 2 5 1 11
        Female
    		 4 4 1 5 14

    End points

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    End points reporting groups
    Reporting group title
    Treatment Sequence 1: ACBD
    Reporting group description
    		 Participants who received a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 1, a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 2, a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 3 and a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 4.

    Reporting group title
    Treatment Sequence 2: BADC
    Reporting group description
    		 Participants who received a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 1, a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 2, a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 3 and a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 4.

    Reporting group title
    Treatment Sequence 3: CDAB
    Reporting group description
    		 Participants who received a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 1, a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 2, a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 3 and a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 4.

    Reporting group title
    Treatment Sequence 4: DBCA
    Reporting group description
    		 Participants who received a single dose of 50 mg mirabegron modified release tablets administered under fed conditions (D) on day 1 of period 1, a single dose of 50 mg mirabegron oral suspension administered under fed conditions (B) on day 1 of period 2, a single dose of 50 mg mirabegron modified release tablets administered under fasted conditions (C) on day 1 of period 3 and a single dose of 50 mg mirabegron oral suspension administered under fasted conditions (A) on day 1 of period 4.

    Subject analysis set title
    Mirabegron Suspension Fasted
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who received mirabegron 50 mg oral suspension under fasted conditions in 1 of 4 treatment periods, taken according to their treatment sequence.

    Subject analysis set title
    Mirabegron Suspension Fed
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who received mirabegron 50 mg oral suspension under fed conditions in 1 of 4 treatment periods, taken according to their treatment sequence.

    Subject analysis set title
    Mirabegron Tablets Fasted
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who received mirabegron 50 mg modified release tablets under fasted conditions in 1 of 4 treatment periods, taken according to their treatment sequence.

    Subject analysis set title
    Mirabegron Tablets Fed
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who received mirabegron 50 mg modified release tablets under fed conditions in 1 of 4 treatment periods, taken according to their treatment sequence.

    Primary: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf) for Mirabegron

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    End point title
    		 Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf) for Mirabegron
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS) which consisted of the subset of participants of the Safety Analysis Set (SAF) population (all randomized participants who received at least 1 dose of study drug) for whom sufficient plasma concentration data were available to facilitate derivation of at least 1 pharmacokinetic (PK) parameter for the fasted mirabegron oral suspension and the fasted mirabegron tablet.
    End point type
    Primary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    19 [1]
    23
    23
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    185.2 ( 87.47 )
    76.37 ( 27.8 )
    391.3 ( 151.9 )
    172.3 ( 83.92 )
    Notes
    [1] - Participants with samples available
    Statistical analysis title
    		 Relative Bioavailability of Mirabegron
    Statistical analysis description
    Relative bioavailability of mirabegron oral suspension formulation vs. tablets when dosed under fasted conditions. AUCinf was analyzed using a linear mixed effects model applied to the natural logarithm log-transformed PK parameter with treatment (suspension fasted, suspension fed, tablets fasted, tablets fed) and investigational period as fixed effects, and subject as a random effect. The number of participants analyzed is calculated by the system and cannot be changed; actual N=23.
    Comparison groups
    Mirabegron Tablets Fasted v Mirabegron Suspension Fasted
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    47.95
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 40.91
         upper limit
    		 56.21
    Statistical analysis title
    		 Food Effect of Mirabegron Oral Suspension
    Statistical analysis description
    Food effect of mirabegron oral suspension formulation. AUCinf was analyzed using a linear mixed effects model applied to the natural logarithm log-transformed PK parameter with treatment (suspension fasted, suspension fed, tablets fasted, tablets fed) and investigational period as fixed effects, and subject as a random effect. The number of participants analyzed is calculated by the system and cannot be changed; actual N=23.
    Comparison groups
    Mirabegron Suspension Fasted v Mirabegron Suspension Fed
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    40.12
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 33.95
         upper limit
    		 47.41

    Primary: Area Under the Concentration-time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast) for Mirabegron

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    End point title
    		 Area Under the Concentration-time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast) for Mirabegron
    End point description
    The analysis population was PKAS.
    End point type
    Primary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    23
    23
    23
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    166.5 ( 82.76 )
    56.55 ( 24.22 )
    370.1 ( 150.8 )
    154.5 ( 82.23 )
    Statistical analysis title
    		 Relative Bioavailability of Mirabegron
    Statistical analysis description
    Relative bioavailability of mirabegron oral suspension formulation vs. tablets when dosed under fasted conditions. AUClast was analyzed using a linear mixed effects model applied to the natural logarithm log-transformed PK parameter with treatment (suspension fasted, suspension fed, tablets fasted, tablets fed) and investigational period as fixed effects, and subject as a random effect.The number of participants analyzed is calculated by the system and cannot be changed; actual N=23.
    Comparison groups
    Mirabegron Suspension Fasted v Mirabegron Tablets Fasted
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    45.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 38.46
         upper limit
    		 52.8
    Statistical analysis title
    		 Food Effect of Mirabegron Oral Suspension
    Statistical analysis description
    Food effect of mirabegron oral suspension formulation. AUClast was analyzed using a linear mixed effects model applied to the natural logarithm log-transformed PK parameter with treatment (suspension fasted, suspension fed, tablets fasted, tablets fed) and investigational period as fixed effects, and subject as a random effect.The number of participants analyzed is calculated by the system and cannot be changed; actual N=23.
    Comparison groups
    Mirabegron Suspension Fasted v Mirabegron Suspension Fed
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    33.54
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 28.68
         upper limit
    		 39.23

    Primary: Maximum Concentration (Cmax) of Mirabegron

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    End point title
    		 Maximum Concentration (Cmax) of Mirabegron
    End point description
    The analysis population is PKAS.
    End point type
    Primary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    23
    23
    23
    Units: ng/mL
        arithmetic mean (standard deviation)
    12.19 ( 9.328 )
    2.54 ( 1.239 )
    35.15 ( 16.26 )
    15.45 ( 9.682 )
    Statistical analysis title
    		 Relative Bioavailability of Mirabegron
    Statistical analysis description
    Relative bioavailability of mirabegron oral suspension formulation vs. tablets when dosed under fasted conditions. Cmax was analyzed using a linear mixed effects model applied to the natural logarithm log-transformed PK parameter with treatment (suspension fasted, suspension fed, tablets fasted, tablets fed) and investigational period as fixed effects, and subject as a random effect. The number of participants analyzed is calculated by the system and cannot be changed; actual N=23.
    Comparison groups
    Mirabegron Suspension Fasted v Mirabegron Tablets Fasted
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    30.76
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 23.76
         upper limit
    		 39.81
    Statistical analysis title
    		 Food Effect of Mirabegron Oral Suspension
    Statistical analysis description
    Food effect of mirabegron oral suspension formulation. Cmax was analyzed using a linear mixed effects model applied to the natural logarithm log-transformed PK parameter with treatment (suspension fasted, suspension fed, tablets fasted, tablets fed) and investigational period as fixed effects, and subject as a random effect. The number of participants analyzed is calculated by the system and cannot be changed; actual N=23.
    Comparison groups
    Mirabegron Suspension Fasted v Mirabegron Suspension Fed
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    22.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 17.35
         upper limit
    		 28.92

    Secondary: Percentage of AUCinf Due to Extrapolation from Time to Last Measurable Concentration (tlast) to Time Infinity (AUC[%extrap]) for Mirabegron

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    End point title
    		 Percentage of AUCinf Due to Extrapolation from Time to Last Measurable Concentration (tlast) to Time Infinity (AUC[%extrap]) for Mirabegron
    End point description
    The analysis population was PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    19 [2]
    23
    23
    Units: percentage extrapolated
        arithmetic mean (standard deviation)
    11.14 ( 4.189 )
    21.7 ( 5.896 )
    6.149 ( 2.74 )
    12.31 ( 5.758 )
    Notes
    [2] - Participants with samples available
    No statistical analyses for this end point

    Secondary: Apparent Total Systemic Clearance After Extravascular Dosing (CL/F) of Mirabegron

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    End point title
    		 Apparent Total Systemic Clearance After Extravascular Dosing (CL/F) of Mirabegron
    End point description
    The analysis population was PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    19 [3]
    23
    23
    Units: L/h
        arithmetic mean (standard deviation)
    329.1 ( 147.1 )
    745.3 ( 276.4 )
    150.3 ( 68.3 )
    364.8 ( 181.9 )
    Notes
    [3] - Participants with samples available
    No statistical analyses for this end point

    Secondary: Terminal Elimination Rate Constant (λz) for Mirabgron

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    End point title
    		 Terminal Elimination Rate Constant (λz) for Mirabgron
    End point description
    The analysis population was PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    19 [4]
    23
    23
    Units: 1/h
        arithmetic mean (standard deviation)
    0.01557 ( 0.00415 )
    0.01657 ( 0.004918 )
    0.01456 ( 0.003525 )
    0.01516 ( 0.004157 )
    Notes
    [4] - Participants with samples available
    No statistical analyses for this end point

    Secondary: Mean Residence Time from the Time of Dosing Extrapolated to Time Infinity (MRTinf) of Mirabegron

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    End point title
    		 Mean Residence Time from the Time of Dosing Extrapolated to Time Infinity (MRTinf) of Mirabegron
    End point description
    The analysis population was PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    19 [5]
    23
    23
    Units: hours
        arithmetic mean (standard deviation)
    58.22 ( 18 )
    64.58 ( 23.42 )
    53.44 ( 15.06 )
    61.01 ( 23.54 )
    Notes
    [5] - Participants with samples available
    No statistical analyses for this end point

    Secondary: Terminal Elimination Half-life (t1/2) of Mirabegron

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    End point title
    		 Terminal Elimination Half-life (t1/2) of Mirabegron
    End point description
    The analysis population was PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    19 [6]
    23
    23
    Units: hours
        arithmetic mean (standard deviation)
    47.89 ( 14.15 )
    46.25 ( 17.12 )
    50.3 ( 12.01 )
    50.02 ( 17.6 )
    Notes
    [6] - Participants with samples available
    No statistical analyses for this end point

    Secondary: Time Prior to the Time Corresponding to the First Measurable (Nonzero) Concentration (tlag) of Mirabegron

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    End point title
    		 Time Prior to the Time Corresponding to the First Measurable (Nonzero) Concentration (tlag) of Mirabegron
    End point description
    The analysis population was PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    23
    23
    23
    Units: hours
        arithmetic mean (standard deviation)
    0 ( 0 )
    0.2 ( 0.3 )
    0.1 ( 0.2 )
    0.7 ( 0.4 )
    No statistical analyses for this end point

    Secondary: Time of Maximum Concentration (tmax) of Mirabgeron

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    End point title
    		 Time of Maximum Concentration (tmax) of Mirabgeron
    End point description
    The analysis population was PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    23
    23
    23
    Units: hours
        median (full range (min-max))
    4.08 (2 to 5.33)
    3 (1.03 to 12)
    4.02 (1.98 to 5.03)
    3.02 (1.98 to 6)
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution During the Terminal Elimination Phase after Extravascular Dosing (Vz/F) of Mirabegron

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    End point title
    		 Apparent Volume of Distribution During the Terminal Elimination Phase after Extravascular Dosing (Vz/F) of Mirabegron
    End point description
    The analysis population was PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 predose, 30 minutes (min), 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 192h, 240h postdose
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    23
    19 [7]
    23
    23
    Units: Liters
        arithmetic mean (standard deviation)
    21663 ( 9196 )
    45348 ( 10665 )
    10688 ( 4932 )
    25559 ( 12989 )
    Notes
    [7] - Participants with samples available
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events

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    End point title
    		 Number of Participants with Adverse Events
    End point description
    An adverse event (AE) was assigned to the last treatment dose received prior to onset (or worsening). A treatment-emergent adverse event (TEAE) was defined as an adverse event which started after first administration of the study drug (day 1 of treatment period 1) up to the end-of-study visit (5 to 9 days after last [early] discharge from the clinical unit). Drug-related events can be possible or probable, as assessed by the investigator, or records where relationship is missing. The analysis population was SAF.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug in first treatment period up to end of study visit in last treatment period (up to 95 days)
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Number of subjects analysed
    25
    24
    23
    23
    Units: participants
        Any TEAE
    13
    11
    8
    8
        Drug-related TEAEs
    2
    1
    4
    2
        Deaths
    0
    0
    0
    0
        Serious TEAEs
    0
    1
    0
    0
        Drug-related serious TEAEs
    0
    0
    0
    0
        TEAEs leading to discontinuation of drug
    0
    0
    0
    0
        Drug-related TEAEs leading to Discont. of drug
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Palatability Visual Analogue Scale (VAS) Scores of Mirabegron (oral suspension)

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    End point title
    		 Palatability Visual Analogue Scale (VAS) Scores of Mirabegron (oral suspension)
    End point description
    Palatability of mirabegron (oral suspension) was assessed using a VAS questionnaire, which consisted of 7 separate VAS scales (bitter, salty, sweet, sour, taste in general, aftertaste and acceptance) which were 100 mm in length (ranged from 0 mm “not at all” or "good" to 100 mm “very much” or "bad"). The analysis population was the SAF.
    End point type
    Secondary
    End point timeframe
    Day 1 postdose of each treatment period
    End point values
    		 Mirabegron Suspension Fasted Mirabegron Suspension Fed
    Number of subjects analysed
    25
    24
    Units: mm
    arithmetic mean (standard deviation)
        Bitter
    26.8 ( 25.2 )
    37.2 ( 30.4 )
        Salty
    13 ( 16.9 )
    13.6 ( 15.9 )
        Sweet
    49.2 ( 26.5 )
    50.2 ( 27.3 )
        Sour
    12.2 ( 18.4 )
    15.2 ( 24.1 )
        Taste in General
    55.2 ( 26.7 )
    56.5 ( 23 )
        Aftertaste
    52.2 ( 29.6 )
    49.5 ( 28.7 )
        Acceptable (for taste and palatibility)
    51.4 ( 27.2 )
    48.7 ( 21.1 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug in first treatment period up to end of study visit in last treatment period (up to 95 days)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Mirabegron Suspension Fed
    Reporting group description
    		 Participants who received mirabegron 50 mg oral suspension under fed conditions in 1 of 4 treatment periods, taken according to their treatment sequence.

    Reporting group title
    Mirabegron Suspension Fasted
    Reporting group description
    		 Participants who received mirabegron 50 mg oral suspension under fasted conditions in 1 of 4 treatment periods, taken according to their treatment sequence.

    Reporting group title
    Mirabegron Tablets Fasted
    Reporting group description
    		 Participants who received mirabegron 50 mg modified release tablets under fasted conditions in 1 of 4 treatment periods, taken according to their treatment sequence.

    Reporting group title
    Mirabegron Tablets Fed
    Reporting group description
    		 Participants who received mirabegron 50 mg modified release tablets under fed conditions in 1 of 4 treatment periods, taken according to their treatment sequence.

    Serious adverse events
    		 Mirabegron Suspension Fed Mirabegron Suspension Fasted Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 25 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 25 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Mirabegron Suspension Fed Mirabegron Suspension Fasted Mirabegron Tablets Fasted Mirabegron Tablets Fed
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 24 (37.50%)
    7 / 25 (28.00%)
    4 / 23 (17.39%)
    7 / 23 (30.43%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 25 (8.00%)
    4 / 23 (17.39%)
    4 / 23 (17.39%)
         occurrences all number
    3
    2
    5
    5
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 25 (8.00%)
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    3
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 25 (4.00%)
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    0 / 23 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 24 (25.00%)
    2 / 25 (8.00%)
    0 / 23 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    6
    2
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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